Septicemia is a clinical syndrome in which infection is disseminated through the body by the blood stream. It is a potentially disastrous blood infection that can be caused by a variety of microorganism. It is a pathological state which results from the presence of microorganisms and/or their poisonous by-products in the blood stream. One particularly common form of septicemia, involving infection by gram-negative bacteria, is referred to as gram-negative bacteremia.
A survey in 1974 reported that septicemia strikes 71,000 people in the United States annually, resulting in death in approximately 25% of the cases. One of the major causes of septicemia is post-operative infection resulting from endogenous bacteria from the respiratory or gastrointestinal tract (See Cruse, P. J. E., et al. Arch., Surg. 107, 106-210, 1973, incorporated herein by reference).
Endotoxemia is a condition caused by the presence of endotoxins in the blood and is commonly associated with severe hypotension that is usually fatal. Shock induced by injecting laboratory animals with endotoxin produces pathophysiologic changes similar to that of gram-negative bacteremic shock in humans. More recently, evidence has suggested that shock syndrome in man is associated with endotoxemia. As in the case of septicemia, endotoxemia affects large numbers of people annually, and is fatal in 60% or more of the cases (see for example RJ Hamill and DG Maki. Endotoxin shock in man caused by gram-negative bacilli. In RA Proctor (Ed), Clinical Aspects of Endotoxin Shock, Vol 4, pp 55-126: 1986. Elsevier, Amsterdam--N.Y.).
In the New England Journal of Medicine, Volume 307, No. 20, Nov. 11, 1982, an article was published by Elizabeth J. Ziegler et al. on the treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. It was disclosed in this reference that septicemia can be treated by injection of anti-endotoxin serum. Hence, the reference does not disclose the use of endotoxin or its derivatives per se, but discloses the use of antibodies directed against endotoxins. This approach was also discussed in an article in Medical World News, June 24, 1985, and a paper by Teng et al., Proc. Nat. Acad. Sci. 82, 1790:1985, wherein it was indicated that monoclonal antibodies (mAbs) against endotoxin are used instead of anti-endotoxin sera. While the antiserum is a highly heterogeneous substance, the mAbs are pure proteins of known structure. Moreover, in these references, the antiserum and the mAbs are used to treat patients suffering from gram-negative septicemia, i.e., they are used therapeutically and not prophylactically.
In an article by A. Balogh et al., Chem. Abstracts, No. 86685(q) Vol. 97, 1982 entitled "Effect of Pretreatment with Radiation--Detoxified Endotoxin on the Endotoxin Shock of Dogs", it was reported that a radiation-detoxified endotoxin preparation identified as "Tolerin" prevented the drop in blood pressure and decrease of cardiac output that appears in the acute phase of endotoxin shock. The endotoxin shock had been induced by administration of Escherichia coli endotoxin.
In another article by A. Balogh, Chem. Abstracts No. 103796x Vol 101, 1982, entitled "Prevention of the Irreversiblity of Surgical Shocks with Radiation Detoxified Endotoxin Pretreatment" it was also reported that gamma-irradiation - detoxified Escherichia coli endotoxin prevented the lethal effects of septic shock in rats and dogs.
Thus, prior to the present invention, the use of Monophosphoryl Lipid A, had not been disclosed in the literature as being useful in preventing septicemia or endotoxemia.
It is therefore an object of the invention to provide a method of inhibiting the onset of septicemia in warm-blooded animals using a therapeutic composition containing Monophosphoryl Lipid A.
It is another aspect of the invention to provide a method of inhibiting the onset of endotoxemia in warm-blooded animals using a therapeutic composition containing Monophosphoryl Lipid A.